The goal of this revised renewal is to continue to investigate how neural and local factors interact to regulate blood flow to human skeletal muscles. The investigators have shown that mental stress evokes atropine sensitive, nitric oxide (NO)-dependent vasodilation in human forearm muscles. Sympathoexcitatory maneuvers (e.g., contralateral ischemic handgrip exercise) can also cause marked NO-dependent atropine sensitive forearm vasodilation after alpha-adrenergic blockade of the forearm. These observations initially led the investigators to hypothesize that there is neurally mediated NO release in conscious humans governed in part by sympathetic-cholinergic nerves. They have now shown that sympathetic withdrawal also contributes to forearm vasodilation during mental stress. This suggests that during mental stress changes in forearm flow and systemic arterial pressure can mechanically stimulate the vascular endothelium to release NO via local cholinergic mechanisms. In this proposal, the investigators explore these alternative mechanisms of NO release by addressing the following specific aims: (1) Is NO-mediated forearm vasodilation observed during contralateral ischemic handgrip exercise after local anesthetic block of the stellate ganglion? (2) Is the forearm vasodilation seen during mental stress after stellate ganglion block NO mediated and atropine sensitive? (3) Is there evidence for vasodilator nerve traffic when mental stress is performed during systemic phenylephrine infusions that raise arterial pressure? (4) Can sympathoexcitatory maneuvers cause NO-dependent vasodilation in the leg? The proposed studies are feasible and address novel concepts in humans. They will allow the investigators to determine the mechanisms responsible for NO-mediated vasodilation during sympathoexcitatory maneuvers (Aims 1-3) and explore their potential whole-body hemodynamic significance (Aim 4). These vasodilating mechanisms may have significance in a variety of disease states associated with endothelial and autonomic dysfunction.